The Gram positive anaerobe C. difficile causes mild to severe antibiotic associated diarrhea, pseudomembranous colitis, toxic megacolon and death1-2. The Rho-glucosylating Toxins A and B (TcdA and TcdB) cause host cell death and profound inflammation and are required for symptomatic infection3-7. Production of the binary toxin CDT (C. difficile transferase) in addition to Toxins A and B by C. difficile is associated with higher mortality, increased peripheral white blood cell count, and elevated risk of recurrence in clinical studies8-10. CDT expressing strains have also become increasingly common over the last ten years, paralleling the overall increase in incidence and severity of CDI, and now account for up to 20% of isolates in the hospital setting11-14 
CDT consists of two components which act cooperatively to intoxicate cells14,15. CDTb, the binding component of CDT, is produced as a precursor protein and requires proteolytic cleavage prior to intoxication. Following cleavage, CDTb associates with the lipolysis stimulated lipoprotein receptor, or LSR, which is required for intoxication16,17. This receptor is highly expressed within the liver, small intestine, colon and various other tissues, and is thought to be involved in the uptake and removal of lipoproteins and in the formation of tricellular tight junctions18,19. Following formation of the CDTb heptamer and binding to LSR, CDTa, the enzymatic component of CDT, then binds the CDTb heptamer. This complex is endocytosed, and endosomal acidification triggers insertion of the CDTb heptamer into the endosomal membrane through which CDTa is released into the cytoplasm20. CDTa then transfers an ADP-ribose moiety to globular actin, which then acts as a capping protein to prevent actin filament elongation. This results in collapse of the actin cytoskeleton, allowing the formation of microtubule protrusions on the surface of host cells which are thought to increase C. difficile adherence21,22.
Although CDT production is associated with more severe disease, the role of CDT during infection is not well understood. In a hamster model of CDI, CDT was shown to enhance virulence in the presence of Toxin A, but not Toxin B. In humans, the intensity of the host inflammatory response is critical in determining disease outcome, and in murine models, innate IL-23 production is detrimental during infection23-26. Toxins A and B shift the immune response towards this pathogenic inflammatory state by inducing IL-1β secretion via activation of the inflammasome26,27.
There is a long felt need in the art for compositions and methods useful for treating or preventing C. difficile infection. The present invention satisfies these needs.